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Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase.

Proceedings of the National Academy of Sciences of the United States of America (2007-07-17)
Scott A Lujan, Laura M Guogas, Heather Ragonese, Steven W Matson, Matthew R Redinbo
RÉSUMÉ

Conjugative transfer of plasmid DNA via close cell-cell junctions is the main route by which antibiotic resistance genes spread between bacterial strains. Relaxases are essential for conjugative transfer and act by cleaving DNA strands and forming covalent phosphotyrosine linkages. Based on data indicating that multityrosine relaxase enzymes can accommodate two phosphotyrosine intermediates within their divalent metal-containing active sites, we hypothesized that bisphosphonates would inhibit relaxase activity and conjugative DNA transfer. We identified bisphosphonates that are nanomolar inhibitors of the F plasmid conjugative relaxase in vitro. Furthermore, we used cell-based assays to demonstrate that these compounds are highly effective at preventing DNA transfer and at selectively killing cells harboring conjugative plasmids. Two potent inhibitors, clodronate and etidronate, are already clinically approved to treat bone loss. Thus, the inhibition of conjugative relaxases is a potentially novel antimicrobial approach, one that selectively targets bacteria capable of transferring antibiotic resistance and generating multidrug resistant strains.

MATÉRIAUX
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Description du produit

Sigma-Aldrich
Ampicillin, anhydrous, 96.0-102.0% (anhydrous basis)
Sigma-Aldrich
Etidronic acid, 60% aqueous solution
Sigma-Aldrich
Methylenediphosphonic acid, ≥99%
Sigma-Aldrich
Nitrilotri(methylphosphonic acid), ≥95% (T)
Sigma-Aldrich
Nitrilotris(methylene)triphosphonic acid solution, 50 wt. % in H2O
Sigma-Aldrich
Iminodi(methylphosphonic acid), 97%
Sigma-Aldrich
Imidodiphosphate sodium salt, ≥97%